43 Standard Medical Therapy for Postpartum Hemorrhage J. Unterscheider, F. Breathnach and M. Geary INTRODUCTION firm contraction of the organ. If severe haemorrhage has already set in, it is highly recommended that the drug should Failure of the uterus to contract and retract following be given by the intravenous route. For this purpose one-third childbirth has for centuries been recognized as the of the standard size ampoule may be injected or, for those most striking cause of postpartum hemorrhage (PPH) who wish accurate dosage, a special ampoule containing and complicates up to 10% of pregnancies globally. In 0.125 mg is manufactured. An effect may be looked for in less the developing world, PPH is responsible for one than one minute.’ maternal death every 7 minutes1. Another uterotonic agent, oxytocin, the hypothalamic In the 19th century, uterine atony was treated by polypeptide hormone released by the posterior pitu- intrauterine placement of various agents with the aim itary, was discovered in 1909 by Sir Henry Dale8 and of achieving a tamponade effect. ‘A lemon imperfectly synthesized in 1954 by du Vigneaud9. The develop- quartered’ or ‘a large bull’s bladder distended with ment of oxytocin constituted the first synthesis of water’ were employed for this purpose, with apparent a polypeptide hormone and gained du Vigneaud a success. Douching with vinegar or iron perchloride Nobel Prize for his work. was also reported2,3. Historically, the first uterotonic The third group of uterotonics comprises the ever- drugs were ergot alkaloids, followed by oxytocin and, expanding prostaglandin family. The prostaglandins finally, prostaglandins. were discovered in 1935 by a group led by Swedish Ergot, the alkaloid-containing product of the fun- physiologist Ulf von Euler10 who found that extracts gus Claviceps purpurea that grows on rye, was recog- of seminal vesicles or of human semen were capable of nized for centuries as having uterotonic properties and causing contraction of uterine tissue and lowering is the substance referred to by John Stearns in 1808 as blood pressure. The term ‘prostaglandin’ evolved from ‘pulvis parturiens’ (a powder [for] childbirth), at which von Euler’s belief that the active material came time it was used as an agent to accelerate labor4. By the exclusively from the prostate gland. This family of end of the 19th century, however, recognition of the ‘eicosanoids’, 20-carbon fatty acids, was subsequently potential hazards associated with ergot use in labor, found to be produced in a variety of tissues and namely its ability to cause uterine hyperstimulation capable of mediating a myriad of physiologic and and stillbirth, had tempered enthusiasm for its use. pathologic processes. Prostaglandins, by virtue of their Focus was diverted toward its role in preventing and ability to cause tetanic myometrial activity, are treating PPH at a time when, according to an 1870 increasingly used as adjunctive therapy to standard report, maternal mortality in England approached one oxytocin and ergometrine to treat PPH resulting from in 20 births5. uterine atony (see Section 8). Attempts to isolate the active alkaloids from ergot This chapter is devoted to critical evaluation of the were not successful until the early 20th century, when standard pharmacological methods available to treat Barber and Dale isolated ergotoxine in 19063. Initially uterine atony, with particular focus on agent selection thought to be a pure substance, this agent was sub- based on effectiveness, safety profile, ease of adminis- sequently found to comprise four alkaloids, and in tration, cost and applicability in low resource settings. 1935 Moir and Dudley were credited with isolating ergometrine, the active aqueous extract ‘to which ergot rightly owes its long-established reputation as UTERINE ATONY the pulvis parturiens’6,7. Moir reported on its clinical use in 1936, stating7: Powerful efficient contractions of the myometrium are ‘. the chief use of ergometrine is in the prevention and essential to arrest blood loss after delivery. The resul- treatment of postpartum haemorrhage. Here the ergometrine tant compression of the uterine vasculature serves to effect is seen at its best. If after the delivery of the placenta the halt the 800 ml/min blood flow in the placental bed. uterus is unduly relaxed, the administration of ergometrine, Recognition of a soft, boggy uterus in the setting of a 1 mg by mouth or 0.5 mg by injection, will quickly cause a postpartum bleed alerts the attendant to uterine atony. 355 POSTPARTUM HEMORRHAGE The particular contribution that uterine atony makes Recognizing the risks of pulmonary embolus and toward PPH is so well known that a universal reflex alloimmunization associated with blood transfusion, action when faced with excessive postpartum bleeding intraoperative cell salvage has recently been intro- is to induce uterine contraction using bimanual mas- duced into obstetric practice in cases where massive sage. Prompt recognition of this condition and institu- obstetric hemorrhage is anticipated or in the manage- tion of uterotonic therapy will effectively terminate ment of patients who decline blood transfusion (see the majority of cases of hemorrhage. Once effective Chapter 72). The fact that uterine atony occurs unpre- uterine contractility is established, persistent bleeding dictably in women with no identifiable predisposing should prompt the search for retained placental frag- risk factors underpins the need for strict protocols for ments, genital tract trauma or a bleeding diathesis. PPH management to be in place in every unit that Astute risk assessment is crucial in identifying provides obstetric care (see Chapters 40 and 41). women at increased risk of uterine atony, thereby allowing preventive measures to be instituted and for OXYTOCIN delivery to take place where transfusion and anesthetic facilities are available. That having been said, one must With timely and appropriate use of uterotonic remember that the majority of parturients with one or therapy, the majority of women with uterine atony more risk factors do not bleed excessively and, con- can avoid surgical intervention. Stimulation of uterine versely, large numbers of women with no risk factors contraction is usually achieved in the first instance experience true hemorrhage. by bimanual uterine massage and the injection of The established risk factors associated with uterine oxytocin (either intramuscularly or intravenously), atony are outlined in Table 1. It is worth noting that with or without ergometrine. The mode of action of multiparity, hitherto believed to be a significant risk oxytocin involves stimulation of the upper uterine factor, has not emerged as having an association with segment to contract in a rhythmical fashion. Owing to uterine atony in recent studies11–13. Whereas previous its short plasma half-life (mean 3 min), a continuous PPH confers a 2–4-fold increased risk of hemorrhage intravenous infusion is required in order to maintain compared to that in women without such a his- the uterus in a contracted state16. The usual dose tory13,14. The presence of leiomyomata may result in is 40 IU in 500 ml of saline, with the dosage rate more than a two-fold increase in the risk for PPH15. adjusted according to response (typical infusion rate It is appropriate that women with these predispos- 10 IU/h or 2 ml/min). When administered intrave- ing risk factors should deliver in a hospital with ade- nously, the onset of action is almost instantaneous and quate facilities to manage PPH. Prophylactic measures plateau concentration is achieved after 30 minutes. include appropriate hospital booking for women at By contrast, intramuscular administration results in a risk and correction of anemia before delivery, active slower onset of action (3–7 min) but a longer lasting management of the third stage of labor, ensuring the clinical effect (up to 60 min). availability of cross-matched blood and access to Metabolism of oxytocin is via the renal and hepatic interventional radiology services and critical care. routes. Its antidiuretic effect, amounting to 5% of the antidiuretic effect of the endogenous peptide hormone vasopressin, can result in water toxicity, especially if Table 1 Risk factors for uterine atony administered in large volumes of electrolyte-free solu- tions. This degree of water overload can manifest itself Factors associated with uterine overdistension Multiple pregnancy with headache, vomiting, drowsiness and convulsions. Polyhydramnios On the other hand, rapid intravenous bolus adminis- Fetal macrosomia tration of undiluted oxytocin results in relaxation of Labor-related factors vascular smooth muscle, which can lead to hypo- Induction of labor tension. The intravenous route is contraindicated in Prolonged labor known hypersensitivity or profound hypotension. It is Precipitate labor therefore best given intramuscularly or by dilute intra- Augmented labor venous infusion. Oxytocin is stable at temperatures up Instrumental delivery ° Manual removal of placenta to 25 C, but refrigeration is recommended if stored for extended periods to prolong its shelf-life. Use of uterine relaxants Disadvantages of oxytocin are its short half-life, Deep anesthesia (especially halogenated anesthetic agents) Magnesium sulfate the requirement for parenteral administration, and the Nitroglycerin need for refrigeration for storage. The use and re-use of syringes in low resource settings carry the risk of Intrinsic factors Previous postpartum